Schizophrenia is a chronic psychotic brain disease of unknown pathophysiology and is one of the top ten leading causes of disability in the United States. An accepted concept is that environmental etiologic factors imposed upon a genetically susceptible background predispose to schizophrenia. Several potential risk genes and risk environmental factors have been identified. Adolescent cannabis use (ACU) has been convincingly shown in several studies to be a risk factor for schizophrenia. Recently, two studies report that the COMT va!158met polymorphism moderates the effects of cannabis (COMT val/val is more sensitive to effects of cannabis) and that this interaction may be important in the pathophysiology of schizophrenia. Our overarching hypothesis is that specific risk genes and specific environment stressors impact brain maturation at a crucial stage of development leading to deficits that predispose to schizophrenia. Our goal is to identify molecular targets involved in the pathophysiology of schizophrenia. We propose to use risk gene and environmental information to advantage molecular discovery in human post mortem tissue. In this application, we propose to use ACU, COMT val158met polymorphism, and the COMT val/val x ACU interaction to identify molecular targets associated with schizophrenia. Adolescence is a time of brain growth, remodeling and development, processes that critically depend on synaptic plasticity. Neurotrophins, such as brain derived neurotrophic factor (BDNF), play essential roles in synaptic function and plasticity. The central hypothesis of this project is that ACU and the COMT val/met polymorphism influence BDNF and its receptor, trk B, predisposing individuals to the development of schizophrenia. Initially we will focus on the hippocampus, a brain region implicated in schizophrenia that expresses high levels of BDNF. We will examine the effect of the COMT genoytpe, ACU and their interaction on BDNF and trk B expression in human post mortem tissue from cases of schizophrenia and controls. BDNF and trk B mRNA and protein will be measured using in situ hybridization, silver grain analyses and immunoblotting. We do not expect BDNF and trkB to be the only molecular targets to be differentially regulated. Thus, we will also use DNA microarray technology to conduct a genome-wide search to detect other novel molecuar targets. This research strategy will allow the identification of novel molecular targets associated with schizophrenia.